The adipose tissue pool in mammals comprises at least two functionally different types of fat: white and brown. Excess white adipose tissue is the defining characteristic of obesity, a pathologic state of increasing severity throughout the world. Brown adipose tissue (BAT) is specialized for energy expenditure and thermogenesis through numerous mitochondria and the expression of the unique uncoupling protein 1 (UCP-1). BAT affects whole-body metabolism, capable of altering insulin sensitivity and modifying one's susceptibility to weight gain. BAT is present in rodents throughout life and has been recently found to be avid for 18F-fluorodeoxyglucose (FDG) and therefore detectable via PET/CT. In contrast, in humans BAT is present in infants, but thought to be nonexistent in adults. Based on our recent findings, we have demonstrated that 18F-FDG PET/CT-evident adipose tissue is in fact BAT and that it substantial amounts are present in over 5% of human adults. We hypothesize that adult human BAT is (1) functional; (2) metabolically relevant; and (3) can be regulated through pharmacological and environmental interventions. The first set of studies (Aim 1) will demonstrate that human BAT generates heat, is associated with insulin sensitivity, and can be activated pharmacologically. The second phase (Aim 2) will probe the ultrastructural and gene expression profile of human BAT. Finally, the murine studies (Aim 3) will establish that BAT mass and activity can be quantified non-invasively via 18F-FDG PET/CT and infrared thermography. We will then determine if pharmacological and nutritional interventions designed to increase BAT mass and activity are effective at improving improved insulin sensitivity and body weight. The studies described in this proposal will enable us to develop a research platform utilizing PET/CT and infrared imaging in both rodents and humans to characterize BAT mass, function, and activation, and identify novel methods to treat obesity and diabetes. PUBLIC HEALTH RELEVANCE: Obesity is the accumulation of too much harmful fat, and it increases the risk for heart attacks, cancers, and diabetes. Recent studies show that adults may have a heat-generating organ known as brown fat. Our research will show that brown fat burns calories and is important for weight loss. The ultimate goal is to find new ways to increase brown fat activity and help obese people lose weight and improve their overall health.